1-[2-(n, n-alkylene-imino)-alkyl]-3-aminoguanidines and intermediates therefor



United States Patent ()fifice 3,l3,59 Patented June 15, 1965 s 139 599 1-[2{N,N-ALKYLENEhR iilJQ-ALKYLj-S-AMINO- GUANIDINES AND lN'I'ERMEDIATES Twan- The present invention concerns amino-guanidines. More especially, it relates to l-R-lower alkyl-3-aminoguanidines, in which R represents N,N-alkylene-imino having from four to ten carbon atoms as chain members, N,N-(N-R -aza-alkylene)-imino having from four to six carbon atoms as chain members, and R representing an organic radical, N,N-bicyclealkylene-imino, in which bicycloalkylene has from five to sixteen carbon atoms as chain and bridge members, and N,N-bicycloalkylene-imino, in which bicycloalkylene has from five to sixteen carbon atoms as chain and bridge members, and N,N-(R -aza-bicycloalkylene)-imino having in the bicycloalkylene portion from four to fourteen carbon atoms as chain and bridge members and R standing for an organic radical, salts or acyl derivatives of such compounds, as well as to process for the preparation of these compounds.

An N,N-alkylene-imino radical, in which alkylene has from four to ten, preferably from six to eight, chain carbon atoms, may be represented, for example, by N,N- tetramethyleue-imino (or l-pyrrolidino), N,N-pentamethyleneimino (or l-piperidino), N,N-hexamethyleneimino (or l-hexahydroazepiuo), N,N-heptamethyleneimino (or l-octahydroazocino), N,N-octamethyleneimino (or l-octahydroazonino), N,N-nonamethyleneimino (or l-decahydroazecino), N,N-decamethylene-imino and the like.

An N,N-(N-R -aza-alkylene)-imino group may be represented by the formula:

cam,

in which each of the letters 12 and 11 represents one of the numbers 2, 3 and 4, with the proviso that the total of n :+n is one of the numbers 4, 5 and 6, and R stands for an organic radical. A more preferred group of N,N- (N-R -aza-a1kylene)-imino radicalstmayrbe represented by the formula:

( Hnm HQ in which each of the letters m and m; represents one of the numbers 1 and 2, and R has the previouslygiven meaning. Such N,N-(N-R -aza-alkylene)-imino radicals are represented, for example, by 4-R -1piperazino, 1-N,N-(3-R -3-aza-1,6-hexylene)-imino, 1-N,N-(4- R 4 aza 1,7 heptylene) imino, l N,N (3 R 3-aza-1,7-hepty1ene)-imino and the like, in which R has the previously-given meaning, and analogous radicals.

Attached to the aza-nitrogen atom of an N,N-(N-R aza-alkylene)-imino group, is an organic radical R which represents primarily an aliphatic radical, and especially lower alkyl having from one to seven, preferably from one to four, carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl and the like, as 'well as n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl and the like, as well as lower alkenyl, preferably allylic lower alkenyl having from three to five carbon atoms, e.g., 2-propenyl (or allyl), 2-methyl-2-propenyl (or 2-methyl-allyl), 2-

butenyl (or 3-methyl-allyl) and the like, lower alkynyl, e.g., ethynyl, l-propynyl and the like, a cycloaliphatic radical, particularly cycloalkyl having from three to seven, particularly from five to six, ring carbon atoms, e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, cycloalkenyl having from five to seven ring carbon atoms, e.g., 2-cyclopentenyl, 3-cyclohexenyl and the like, or any other suitable aliphatic radical.

The above-mentioned aliphatic, particularly lower alkyl, groups representing R in the above formulae may be substituted, for example, by other aliphatic radicals, such as cycloaliphatic groups, primarily cycloalkyl and cycloalkenyl as defined hereinabove, carbocyclic aryl, particularly monocyclic or bicyclic carbocyclic aryl, e.g., phenyl, l-naphthyl or 2-naphthyl, as well as substituted pheuyl, substituted l-naphthyl or substituted Z-naphthyl. Substituents attached to the carbocyclie radicals are, for example, lower alkyl, e.g., methyl, ethyl and the like, lower alkoxy, e.g., methoxy, ethoxy and the like, lower alkylenedioxy, e.g., methylenedioxy and the like, lower alkylmercapto, e.g., methylmercapto, ethyl-mercapto and the like, nitro, amino, particularly N,N-di-substituted amino, such as N,N-di-lower alkyl-amino, e.g., N,N-dimethylamino, N,N-diethylamiuo and the like, halogeno, e.g., fiuoro, chloro, bromo and the like, trifiuoromethyl or any other suitable substituent. Groups attached to carbocyclic portions may be in any of the available positions, whereby one or more than one of the same or of difierent substituents may be present. Other substit uents attached to an aliphatic, particularly a lower alkyl, group are heterocyclic aryl radicals, such as monocyclic azacyclic aryl, for example, pyridyl, e.g., 2-pyridyl, 3- pyridyl, 4-pyridyl and the like, bicyclic monocyclic azacyclic aryl, for example, quinolyl, e.g., Z-quinolyl and the like, monocyclic diazacyclic aryl, e.g., 3-pyridazinyl, Z-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl and the like, monocyclic thiacyclic aryl, for example, thienyl, e.g,, Z-thienyl and the like, monocyclic oxacyclic aryl, for example, furyl, e.g., Z-furyl and the like. These heterocyclic aryl radicals may also have additional substituents, such as, for example, those attached to the above-described carbocyclic radicals.

An aliphatic radial R in the above formulae, particularly a lower alkyl radical may also be substituted by functional groups, such as, for example, hydroxyl, etherified hyd-roxy, such as lower alkoxy, e.g., methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and the like, polyalkylenediox e.g., polyethylenedioxy, polypropylenedioxy and the like, which polyalkyleneoxy radicals may have from two to twenty lower alkyleneoxy portions and may have a free terminal hydroxyl group or an etherified terminal hydroxyl group, such as a terminal lower alkoxy, e.g., methoxy, ethoxy and the like, group, carbocyclic aryloxy, such as monocyclic carbocyclic aryloxy, e.g., phenyloxy and the like, or carbocyclic aryl-lower alkoxy, such as monocyclic carbocy-clic aryllower alleoxy, e.g., benzyloxy, diphenylmet-hoxy, (4- chlorophenyl) -phenyl-methoxy and the like, or esterified hydroxyl, such as lower alkoxy-car-bonyloxy, e.g., Inethoxy-carbonyloxy, ethoxy-caribonyloxy and the like, carbamyloxy, such as carlbamyloxy, or N-lower alkyl-cararyl-amino, particularly N-monocyclic carbocyclicaryL amino, e.g., N-phenylamino and the like, N carbocyclic 'aryl-lower aliphatic hydrocarbon amino, particularly N-monocyolic carbocyclic-lowerr alkyl-amino, such as n'eimino, in which alkylene has 'from four to six carbon atoms as ri'ngfrnernber's, such as, for example, l-pyrrolidii io i grou'ps, eigh, l-pyrroli'dino, 2-rnethyl-1-pyrroliclino and the like, l-piperidino radicals, e.g., l-piperidino, 2- methyl-l-Iiipelidino, 3 methyl-:l-piperidino, 4'-r'nethyl-'1- pi-peridino, 3-hydr'oxy-1 pi ieridino, 3-acetoXy-l-piperidiho, '3 hydroxymeth hl-piperi'dino and the like, 1-N,N 1, 6;heXylene)-'imino, '4-m'orph'oli'no, or l-piperazino ls, particularly 4-l0Werjalkyl 1 piperazino, e.-g., 4- rhethyl l pip'era'zino, 4fethyl -l-pipera'zin'o, 4-(2-hydroxyt hyD-l-piperaz-ino, 4-(2 acetoxyethyl)-l -piperazino, 4- [2-(w-methoXy=poiyethyleneoxy)-ethyl]-1 piperazino and the like, 'm'ercapto, etherified mercapto, especially lower alkyl-n'ierc'apto, 'e'.g., methyl-mercapto, ethyl-mercapto and the like, halogefno atoms, 'e.g., tluoro, chlo'ro, atoms and the like, whereby jon'e 'o'r mo'r'e than one functional group may be attached to one or more than one carbon ato'rnof an aliphatig'particularly lower 'alkyl, radical.

The grou R1 in the aboyeformulae may also represent cairbocyclic 'ary], primarily monocyclic carbocyclic aryl; fe'jgl, fphe'ny-l, or bicy'cli'c 'c'a'rbocyclic aryl, e1g., lnafihthyl or 2-i1aphthyl, which radicals mayhave 'one or tiriore'th'an one of, the same orfditfefent 'substitue'nts attached to'a'nyof the available Carbon atoms; 'substituents are, rarer-am l those previously-described as being atracked-1o a caibocyclic 'a'ryl radical. -Itfalso represents hefe'ro'cyclic ar'yl, p'rirna r-ily monocycl-ic orbi'cyolic heterocy'lic 'a'r'yl, which have one or more than one-sulfur, oxy

gen and/"or nitrogen atom fas ring members, such as, for example, monocy-clic mono-azacyclic aryl, for example, pyridy1,*e.g., Z-pyridyl, 3-pyridyl, 4-pyridyl' and the like, hicyclic mono-'azacyclic aryl, for example, quinolyl, e.g.,

2-quinolyl, 4-quinolyl and the like, monocyclic 'di-azacyclic aryl, for example, pyridazinyl, e.g., 3-pyridazinyl andth'e like, pyrimidyl, e.g., 2-pyrimidyl,-4pyrimidyl and example, thieriyl, e.g., 2-thienyl and the like, "or monoeyclic okacyclic aryl, for'example, furyl, e.g., 2-furyl and the like, and these heterocyclicradicals substituted by substituents, such as, for example, those' -rnentioned hereinbefore. 7 V a V V a An N,N-bicy-cloalkyleneimino radical may be represented by the formula:

inwhich A stands for an alkylene radical, which links the C -canbon atom with the C -carbon atom' and has from one to five oarbdn ato ms, or an alkenylene radical, which links the (l -car bou atom with'th'e C -canbon atom and has-from two to five'carbon atoms, A represents a direct-bond between the C -carbon atom and the'C -carhon atom, or any alkylene radical, which'separates the C -carbon atom from the C -canb0n atom by from one to twolcarbon atoms and has a total of from one to six carbon atoms, and each of the groups A represents a i the like, pyrazinyl, e.g., 2-p-yrazinyl and the like, pyrryl,

e.g., '2-pyrry1 and the like, monocyclic thriac'yclic ar'yl, for;

direct bond between the imino-nitrogen atom and one of the .bridge carbon atomsv C and C or an alkylener-adi- 5 cal which links the C -carbon atom or the Cg carbon atom with the imino-nitrogen atom and has from one to three carbon atoms, with the proviso that whenever the carbocyolic ring I has from three to fiveatoms as ring members,

the a'zacy'clicring II has atleast five atoms asi'ing m'mhers. I 7

An N,N4hicycloalkylene-imino radical stands primarily for one of the formulae:

which formulae each of the grouos R; Rfii'f' and R"" stands for hydrogen or methyl, and withtlie pro-2f viso that whenever the carbocyclic ring I has] five atoms as ring members; the, -azacyclic ring II has at least five atoms as ring members. 7

Such N,N-bicycloalkylene-imino radical's'are represent-j.

, 1,8,8-trimethyl-3-aza 3-bicyclo[3,2,1]octyl, V

and the like aswell as (or 1,2,3,4,5,8,9,1'O octahYdrO-l-quinolinyl'), r

5 8-aza-8-bicyclo [4,4,0] dec-3 -enyl (or 1,2,3,4,5,8,9, l -octahydro-2-isoquinolinyl) 3-aza-3-bicyclo[3,2,1] oct-6-enyl and the like.

An N,N-aza-bicycloalkylene-imino radical is primarily a radical of the formula:

in which R A and A have the previously-given meaning, each of the group A, represents a direct bond between the C -carbon atom and the C -carbon atom, respectively, and the aza-nitrogen atom carrying the group R or an alkylene radical, which connects the c -carbon atom and the C -carbon atom, respectively, with the aza-nitrogen atom carrying the group R and has from one to two carbon atoms, with the proviso that at least one of the groups A and A represents an alkylene radical having from one to two carbon atoms, and with the further proviso that whenever the azacyclic ring having as the ring member the nitrogen atom carrying the group R i.e., ring I, has four ring members, the azacyclic ring having as the ring member the nitrogen atom carrying the an'iino-guanidino-lower alkyl group, i.e., ring 31, has at least four ring members.

An N,N-aza-bicycloalkylene-imino portion is more in which each of the groups R, R, R", R" and R have the previously-given meaning, and with the proviso that whenever the azacyclic ring having as the ring member the nitrogen atom carrying the group R i.e., ring I, has four atoms as ring members the azacyclic ring having as the ring member the nitrogen atom carrying the aminoguanidino-lower alkyl group, i.e., ring II, has at least four ring members.

Specific examples of N,N-aza-bicycloalkylene-imino radicals are, for example, 2,5-diaza--R -2-bicyclo [2,2,0] hexyl, 4,8-diaza-4-R -9-bicyclo[4,3,0]nonyl (or 5-R -2,3, 4,5,6,7,8,9-octahydro-lH-pyrrolo[3,4 c]pyridyl) 2,7-diaza-7-R -2-bicyclo [4,4,0] decyl (or 5-R -l,2,3,4,5,6,7,8,9, 10-decahydro-l'isonaphthyridyl), 3,7-diaZa-7-R 3 bicyclo[3,3,l]nonyl (or 7-R -3-bispidinyl) and the like.

The carbon atoms of an N,N-alkylene-imino, an N,N- (N-R -azaalkylene)-imino, an N,N-bicycloalkylene-imino, or an N,N-(N-R -aza-bicycloalkylene)-irnino may be substituted by aliphatic radicals, such as lower alkyl, particularly, methyl, as well as ethyl, n-propyl, isopropyl and the like. Furthermore, one or more than one pair of neighboring carbon atoms of an alkylene portion in any of the above imino groupings may be part of a monocyclic carbocyclic aryl, particularly phenyl, nucleus, which may have additional substituents, such as those described hereinabove. Such carbocyclic aryl nuclei are preferably fused-on to the N,N-alkylene-imino groups, and resulting bicyclic groupings may be illustrated, for example, by 2- isoindolinyl, l-indolinyl, l-tetrahydroquinoyl, 2tetrahydrosioquinolinyl, l-N,N-benz[b]hexamethylene-imino, 1-

' N,N-benz[c]hexamethylene-imino, 1-N,N benz[d]hexamethylene-imino, 1-N,N-benz [b]heptamethylenedmino, 1- l N,N-benz[cJheptamethylene-imino, 1-N,N-benz[d]heptal methylene-imino, 1-N,N-dibenz[b,f]hexamethylene-imino, l-N,N-dibenz[c]heptamethylene-imino and the like, as well as these groups, in which the fused-on arly portion, particularly benz-nucleus, is substituted, whereby one or more than one of the same or of difierent substituents selected from the afore-mentioned class may be attached to any of the positions available for substitution.

The lower alkyl radical, linking R with the aminoguandino group, is represented by lower alkylene having from one to seven carbon atoms. Preferably, lower alkylene has from two to three carbon atoms, which separate the group R from the amino-guanidino group by the same number of carbon atoms; such radicals are 1,2-ethylene, 1- 1ethyl-l,2-ethylene, 2-methyl-1,2-ethylene or 1,3-propylene. Other lower 'alkylene radicals are, for example, methylene, 1,1-ethylene, 2,3-butylene, 1,3-butylene, 1,4- butylene, 1,4-pentylene, LS-pentylene and the like.

The l-arnino-guandino group may be represented by the formula:

NR5 NC R4 v I ia \NHN/ in which each of the groups R R R and R stands primarily for hydrogen, but may also represent an organic substituent, such as, for example, an aliphatic group, particularly lower alkyl, e.g., methyl, ethyl, n-propyl, isopropyl and the like, as well as a carbocyclic aryl radical, particularly monocyclic carbocyclic aryl, e.g., phenyl, or phenyl substituted by one of the previously-mentioned substituents, or a carbocyclic aryl-aliphatic radical, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g., benzyl, l-phenylethyl, Z-phenylethyl, diphenylmethyl and the like, and analogous radicals, in which the phenyl portion is substituted by any of the previously-described substituents. One of the groups R and R may also represent an acyl radical, particularly the acyl radical of an organic carboxylic acid, such as a lower aliphatic carboxylic acid, for example, a lower alkanoic acid, e.g., acetic propionic, pivalic acid and the like, a substituted lower alkanoic acid, e.g., chloroacetic, dichloroaeetic, hydroxyacetic, methoxy acetic, cyclopentyl-propionic acid and the like, or a lower alkenoic acid, e.g., 3-butenoic acid and the like, a carbocyclic aryl carboxylic acid, for example, a monocyclic carbocyclic aryl carboxylic acid, e.g., benzoic, hydroxybenzoic, 4-methoxybenzoic, 3,4-dimethoxy-benzoic, 3,4,5-trimethoxy-benzoic, 4-O-ethoxycarbonyl-syringic, 3,4-dichlorobenzoic, 3-N,N dimethylamino-benzoic, 4-nitrobenzoic acid and the like, or a bicyclic carbocyclic aryl carboxylic acid, e.g., l-naphthoic, Z-naphthoic acid and the like, or a heterocyclic aryl carboxylic acid, for example, a monocyclic heterocyclic aryl carboxylic acid, e.g., nicotinic, isonicotinic, 2- furoic acid and the like. The amino-guandino group is more especially the group of the formula:

Salts of the new compounds of this invention are particularly pharmacologically and therapeutically acceptable, non-toxic acid addition salts, such as those with inorganic acids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, with organic carboxylic acids, e.g., acetic, prop-ionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, dihydroxyrnaleic, 'fumaric, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, mandelic, salicyclic, 4-aminosalicylic, 2-phenoxybenzoic, Z-acetoxybenzoic acid and the like, or organic sulfonic acids, e.g., methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic,-ptoluene sulfonic acid and the like. Monoor poly-salts may he formed.

The new compounds of this invention and the salts thereof cause in the anesthetized, normotensive dog an inhibition of the carotid occlusion reflux pressor response and antagonize pressor responses elicited by high doses '2 of amphetamine, and lower the arterial iunanesthetized' renal or neurogenic hypertensive dog. These efi'ects appear to ibe due to an inhibition of the releaseand/ordistribution of transmitter substances from sympathetic nerve terminals. In view of the fact that the compounds of this invention block the hypertensive effects of these pressor substances, they can, therefore, be used as larrtiliypertensive. agents to relieve hypertensive conditions, particularly those of neurogenic, renalor-essential nature In addition, compounds'of this invention cause an increase in peripheral bloodfiow, and can, therefore, be used in functional peripheral vascular diseases, suc as Raynauds disease and the like. a V

A preferred group of compounds of this invention are represented by the compounds of the formula:

in which R has the previously-given meaning, the latter n stands for 6, 7 and 8, and A represents lower alkylene having from two to. three carbon atoms. and separating.

methylene-imino) pro'pyl] -guanidine,. 3-amino-1-[3-( l-N,

N-heptamethylene-imino) propyl] -guanidine, 3 amino-l [-(l -N,N-ootamethylene-irnino) .-ethyl] ,-guan-idine and the like, and pharmacologically acceptable acid addition salts thereof, particularly thosewith. suitable mineral acids. Another group of preferred compounds of this invention may be illustrated by the formula:

in Which A- and each of the letters in, and m have the previous-given meaning," and R1 stands for lower alkyl having preferably from one to four. carbon atoms, e.g.,' .methyl, ethyl, n-propyl, i'sopropyl, n-butyl and. the like;

pressure inthe 1 and pharmacologioally acceptable acid addition salts thereof. Specific compounds of this group are, for example,

3. amino-1-[2 (4 methyll-piperazino)-ethyl]-guanidine, 3- arnino ,l[3-(4-rnethyl-lkpiperazino)-propyl] -guanidine, 3amino-1-[2r4 ethyl l-piperazino)-ethyl] guanidine,

3 amino l-[2-(4-isopropyl-l-piperazino)-ethyl]guanidine, 3-amino-1-{2-[ 1-N,N-(3-aza-3-methyl-hexaniethylone -imino] -ethyl}-guanidine, 3'-amino-1-{2-[1-N,N-1-(4- aza 4-methyl-heptamethylene -imino] -ethyl}-guanidine and the like,and pharmacologically acceptable acid addition-salts thereof, particularly with suitable mineral acids,

Thecompounds of this invention may be used in the form of pharmaceutical preparations, which contain the neWamino-guanidine compounds or the pharmacologically acceptable acid addition salts thereof. in. admixture with an organic or inorganic, solid or liquid" carrier suitable for external or parenteral administration. For makingup the preparations there may be employed substances which, do notreact with the new compounds, such as water, gelatfiie, lacetose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzylalcohols,

. gums, propylene glycol, polyakyl ene glycols or any other kho'wn'carrier used for'such preparations. The latter may be in the solid form for example, as capsules, tablets,

drag ees and the like, or. in liquid form for example, as'

solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting emulsifying agents and the like,

. 8'- salts for varying the osmotic may also contain, in combination, other pharmacologically acitve substances. I

The amino-guanidine compounds of this inventionmay" be prepared, forexample, by convert-ing in an R-lower alkyl-amine, in which R has'the above-given. meaning, or a salt thereof, the amino group-into an amin'mguani dino group and, if desired, converting a resulting salt into the free compound, and/or, if desired, converting a resulting compound into asalt or an acyl derivative thereof. The reagents of choicefor the conversion of an amino group into an amino-guanidino group are S-lower alkyl-Z- isothiosemicarbazides particularly those of the formula:

N 'R5 Ru-S-C' R4 NH-N V v i R3 t in which R R and R havegthe'previouslyegiven. mean ing, and R stands for lower alkyl, particularly; methyl, as Well as ethyl, n-propyl; isopropyl' and'ithe-like, and' acid. addition salts thereof. The salts," which are ,e'nr-f ployed in preferenceover the free base, are-primarily those with mineral acids, e-.g-., hydrochloric,' hydrobromic, hydriodic, sulfuric acid and the like-.1 The. preferred reagents are acidaddition salts of S-IDQthYLZdSOtHlOSEHTl carbazide 'with mineral acids, suchasp the hydriodide, sulfate: and the like. The starting materiahinwhicli the group is above-all an unsubstituted. amino group,: but may also represent a substitutedaminogrtmp having R as the substituent, is generally used in the forn'rof its free base. 7 I

The reaction is" carried out by contacting the starting material with the reagent, preferably in the presence of an inert solvent, the choice of which depends primarily on the solubility of the reactants. Water or Water-miscible organic solvents, such aslower alkanols, e.g., methanol, ethanol, propanol, isopropanol, tertiary butanol and the like, ethers,'e.g., diethyleneglycol dimethyl-ether,

p-dioxane, tetrahydrofur'an. and the like, ketones; e-;g.,;

acetone, ethyl methylketone andthe like, lower'alkanoic acids, egl, acetic acid and the like, formamides, e.g.,f

diluent s.

gas, e.g., nitrogen, and/ or in a closed vessel. 7 Analogous reagents capable of converting 'anramino group into an amino-guanidino group arethe O-loweraalkyl 2 isosemicarbazides,

particularly those of 'the formula:

'in which R R R and RB have the previously -given meaning, or salts thereof withmineral acids: These the like, r'epreselit's a preferred reagent.

.semicarbazide derivatives are used in'tlie' same way as-the above-described, corresponding l-amino-Z-isothiou'rea reagents; an'acid addition salt-of O methyla-isosemicarhae zide with a mineral acid, e.g., hydriodic, sulfuric-acid and pressure;-butfers, etc, They- I The above-describedreagents are'fknown, or,.'if 'new, maybe prepa'redaccordiiig'tof procedures described in the.

prior art and llS'QdJfQfllhfi manufacture of known analogs;

for example, the Slower alkyl-Z-isotliiosemicarbazides or .1

O'-lo wer h alkyLZ-isoshficarbazides may be manufactured by' alkylating thiosernicarbazides or semicarbazides with alower alkyl halide, e.g., methyl or ethyl chloride, bromide or iodide and the like, or with a di-lower alkyl sulfate, e.g., dimethyl sulfate,'diethyl sulfate 'andthe like.

The starting materials, i.e., the R-lower alkyl-amines, in which R has the previously-given meaning, used in the above procedure are known or may be prepared according to known procedures. They may, for example, be obtained by treating a compound of the formula RH, in which R has the previously-given meaning, with a halogeno-lower alkano-nitrile, in which halogen represents, for example, chloro, bromo, and the like, or with a lower alkeno-nitrile, in which the double bond is activated by the nitrile group in such fashion, that it adds to the imino group. In a resulting R-lower alkano-nitrile, the cyano group is then converted into a methyleneamino group by reduction, for example, by catalytic hydrogenation, such as, treatment with hydrogen in the presence of a catalyst containing a metal of the eighth group of the periodic system, e.g., palladium on charcoal, Raney nickel and the like, or, preferably, by treatment with a suitable light metal hydride, for example, an aluminum hydride, e.g., lithium aluminum hydride, sodium aluminum hydride, magnesium aluminum hydride, aluminum borohydride, aluminum hydride and the like, which hydrides may be used, if necessary, in the presence of an activator, such as aluminum chloride and the like.

The compounds of the present invention may also be prepared, for example, by converting in a l-R-lower alkyl- 3-X-guanidine, in which R has the previously-given meaning, and X stands for nitro or nitroso, or a salt thereof, the grouping X into an amino group, and, if desired, carrying out the optional steps.

The conversion of a nitro or a nitroso group into an amino group may be carried out by per se conventional reduction methods. For example, reduction may be achieved by treatment with nascent hydrogen; the latter may be generated by contacting a suitable metal or metal compound with a hydrogen donor, for example, a suitable metal, e.g., zinc or any other analogous metal, with an acid, e.g., acetic acid and the like, zinc acetate or any analogous metal compound with water or a moist solvent,-

or any other equivalent metal-hydrogen donor combination, such as, for example, an alkali metal, e.g., sodium and the like, in the presence of liquid ammonia and an ammonium compound, e.g., ammonium chloride and the like. Treatment with hydrogen in the presence of a catalyst, e.g., nickel and the like, may also be used in the above conversion of a nitro or a nitroso group into an amino group; reduction of a nitro-guanidino group in neutral or basic medium leads first in the formation of a nitroso-guanidino group, whereas reduction in an acidic medium yields directly the desired amino-guanidino group. The reduction procedure may also be carried out electrolytically.

The starting materials, which are new and intended to be included within the scope of this invention, may be prepared, for example, by reacting an R-lower alkyl-amine with an S-lower alkyl-l-nitro-Z-isothiourea or an S-lower alkyl-2-nitroso-2-isothiourea or acid addition salts of such reagents; the reaction may be carried out according to the previously-described treatment of an amine with a l-amino S lower alkyl 2 isothiourea. The corresponding O-lower alkyl-l-nitro-Z-isoureas or O-lower alkyl-l-nitroso-Z-isoureas may replace the 2-isothiourea reagents.

Preferred l-(R-lower alkyl)-3-nitro-guanidines and l- (R-lower alkyl)-3-nitroso-guanidines used as the starting materials are, for example, those of the formula:

(damn-1) in which R, A and the letter nhave the previously-given meaning, and acid addition salts thereof. Such compounds are, for example,

l-[2-(l-N,N-hexamethylene-imino)-ethyl]-3-nitro guanidine,

1-[3-(N,N-hexamethylene-imino)-propyl] 3 nitro guanidine,

1-{-2-[1-N,N,-(3-methyl-hexamethylene)-imino] ethyl}- S-nitro-guanidine,

l-[2-(l-N,N heptamethylene imino) ethyl] 3 nitroguanidine,

1- [2-(1-N,N-heptamethylene imino) propyl] 3 nitroguanidine,

1-[3-(l-N,N-heptamethylene-imino) propyl] 3 nitroguanidine,

l-[2-(1-N,N octamethylene imino) ethyl] 3 nitroguanidine and the like, and

1-[2-(1-N,N-hexamethylene-imino) ethyl] 3 nitrosoguanidine,

1-[3-v(1-N,N-hexamethylene-imino) propyl] 3 nitrosoguanidine,

1-{2-[1-N,N-(3-methyl-hexamethylene) imino] ethyl}- B-nitroso-guanidine,

l- [2-(l-N,N heptamethylene imino) ethyl] 3 nitroguanidine,

l- [2-(l-N,N-heptamethylene-imino)-propyl] 3 nitrosoguanidine,

l-[3-(l-N,N-heptamethylene-imino)-propyl] 3 nitrosoguanidine,

1-[2-(1-N,N-octamethylene-imino) ethyl] 3 nitrosoguanidine and the like, and acid addition salts of such compounds.

Another group of preferred starting materials are those having the formulae:

in which R A and the letters m and m have the previously-given meaning, and acid addition salts thereof. Specific starting materials are, for example,

1- [=2- (4-methyll-piperazino -ethyl] -3-nitro-gu anidine,

l- [3-(4-methyl-1-piperazino) -propyl] -3-nitro-guanidinc,

l- [2- (4-ethyll-piperazino) -ethyl] -3 -guanidine,

1- [2- (4-isopr-opyl-l-piperazino -ethyl] -3-nitro-guanidine,

1-{2- l-N,N- 3-aza-3 -methyl-hexamethylene -imino] ethy1}-3 -nitro-guanidine,

1-{2-[ 1-N,N-(4-aza-4-rnethyl-heptamethylene)imino]- e-d1yl}-3-nitro-guanidine and the like, and

1 [2- (4-methyl-l-piperazino) ethyl] -3-nitroso-guanidine,

l- 3- (4-methyl-l-piperazino) -propy1] -3-nitroso-guanidine,

1- [2- (4-ethyl-l-piperazino -ethyl] -3-nitroso-guanidine,

1- [2- (4-isopropyll-piperazino -ethyl] -3-nitroso-guanidine,

1-{2-[ l-N,N- (3 -aza-3-methyl-hexametl1ylene)-imino]- ethyl}-3-nitroso-guanidine,

1-{2-[ l-NJ'J-(4-aza-4-methyl-heptamethylene -imino] ethyl}-3 -nitroso-guanidine and the like, andacid addition salts of such compounds.

The new compounds may be obtained in the form of the tree compounds or as the salts thereof. A salt may be converted into the free compound in the customary way, for example, by treatment with a strong alkaline reagent, such as aqueous alkali metal hydroxide, e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, or a strong quaternary ammonium anion which not all of the salt-forming basic groups participate in the salt formation.- Such'salts may then'be treated'with an acid in order to form compounds, in which all ora g'reaternumber the basic" groups'takepart in the salt formation. e

Acyliderivatives of thecornp'oundofthis invention, i;e.", 1

compounds of the previous formula, in which one of the groups R and R5, may be prepared, for example, by'tr'eau' ing the amino-guanidine compound with the reactive derivative-of a carboxylic acid, for example, with the halide,

e.g. chloride and the like, or the anhydride thereof. It maybe performed in the presence of aninert solvent, for example, in a hydrocarbon, such as a lower alliane elg pentan'e; hexane "and-the like; or a monocyclic 'carbo cyclic a-ryl hydrocarbon, egg, benzene; toluene, xylene and the like or a tertiary organic base, such as a liquid pyri dine compound, e.g., pyridine, collidine and the like Acylation may also be achieved in the absence of a solvent, for example, by treating the aminc-guanidine compound or a salt thereof with the ac ylating reagent, 'for example, acetic acid anhydride in a sealed tube.

"The invention also comprises any modification of the general process wherein a compound obtainableasan intermediate at any stage of the process is used as startin gmaterial and the'remaining step(s) of the process is (are) carried out, as well as any new intermediates. 7

In the process of this invention such starting materials are preferably used which lead to" final products mentioned in'the beginning as'prferred embodiments of the invention.

This is a continuation-inpart application of my appli- 4O cation Serial No. 76,480, filed December 19, 196-0, and" now abandoned;

The following examples illustrate the invention-and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade. 4:5

' Example 1 l A mixture of 3.12 g. (0.02 mol) of 2-(N,N-hepta-, methylene-imino)-ethyl-amine and 4.665;. (0.02 mol) of S-methYl-Z-isothiosernicarbazide hydriodide in 10 Water is refluxed'for four hours and is then cooled. The solid material is filtered off and the resulting 3-amino-l- [2-(N,N-heptamethylene-imino)-ethyl]-guanidine liYdriodide ofthe formula:

is recrystallized from a mixture of ethanol and diethyl-f product solidifies upon,standing,'M.P. 53-56%.

ether, M.PL 129-131; yield: 3 g.

The starting material used in the above reaction may be prepared as follows: To a solution of 73 g. of chloroacetonitrile in 500 ml. of benzene are added 51.5 g. of anhydrous sodium carbonate and a solution of 109.2 g. of N,N'-heptamethyleneimine in 250 ml. of benzene. The reaction mixture is refluxed for four hours-While stirring. After cooling, filtering and concentrating under reduced pressure; the oily; residue. is distilled'to yield the colorless l.- N,N- heptarnethyleneimino) acetonitrile, B.P. 114- l-l8/14 mm.; yield: 127.5 g. a

To a-suspension of 44:5,g. of lithium aluminum hydride in 2000 ml. of ether is addedasolution of 127.5 g. of- (1 N,N-heptamethyleneimino)-acetonitrile in 300 ml. of ether'while cooling. After completing the addition, the .75

. 53 ml. of water.

. l2 solution is refluxedifor three hours and stirring is-continned overnight. In succession, 40ml. of-water, 50 ml.' of 20% aqueous 'sodium'hydroxide and 125 mlpof water are added while cooling, The reaction niixture is filtered, the filtrate is concentrated under reduced pressure; and the desired 2-( l-N,N-hepta-methyleneimino)-ethylamine isdistilled, B:P. 108-111/14 mm.; yield: 115.7. g.

12 g. of .1-[2-(N,N-heptamethylene-imino)-ethyl]-3- nitro-guanidine and 17 g. of zinc.dust are vmixedin a. mortar with water to form a thick. paste, which .is then. added to 5 ml. of acetic acid while stirring- The tempera tu're is held between 0 and 10 during the-mixing of the; reagents and is then allowed toslowly rise to. room;.t'empe'rature.- The reactionmixture is thenw'armed .to 40 on the steam bath and held at that temperature ford'ifteen minutes.- The solidmaterial isfilteredofi, the filtrate is. concentrated underreduced pressure't'o .yield an acetate salt of 3 -amino- 1- [2 (N,N-heptarnethylenevimino) ethyl] guanidine, which iscon-verted to the product ofEx'ample. 1 by, treatment with 6 N hydriodic acid. p 0

The starting material isp'repar ed as follows: Amixture of 5.2g. (0.033 mol) of 2.-(N,Nrheptamethyleneaimino)- ethylarnine and 3.6 g. (0.027 mol) of srrnethyl-l nit'roar, isothiourea. in ml'. ofjethanol is'refluxed-iortour hours. After cooling 5.2 g. of -l-[2-(N,N -lieptamethylene-imino)-ethyl]-3-nitro-guanidine of the formula: 5

is filtered oii 183 7 H CN which melts atlas-172?.

The starting material may be prepared as followsz V 50.4 g. of chloroacetonitrile is added dropwise to a solutionzof 133. g. of 4-methyl-piperazine in l00 ml. of etha-,

nol. The mixture is refluxed, stirred fortwo hours and allowed to. stand overnight.- The solutionis concentrated under reduced pressure, the residueis treatedwith i 270 ml. of 30 percent aqueous sodiumhydroxide while cooling and then extracted with ether. The ether phase is'dried over solid. sodium hydroxide, the solvent'isremoved, andthe residue fractionated to yield the l-methylpiperazino-acetonitrile, B.P. -125./.12' mm. The- A-solution of 50 g. of 4-methyl piperazino-acetonitrile in 400 ml. of anhydrousether is addedito 1000 ml. of anhydrous'ether containing 19 g, of lithium aluminum. hydride while cooling and stirring. The reaction mixture is then refluxed for'6 hours, allowed to stand overnight and decomposed by successive addition of 17 ml. of Water, 20 ml. of20 percent aqueous sodium hydroxideand The mixture is filtrated, the filtrate is" evaporated and the residue is distilledto yield the desired alkylene-imino, in which alkylene has from four to ten chain carbon atoms, and the amino-guanidino group has the formula in which each of the groups R and R is a member selected from the group consisting of hydrogen, lower alkyl- 3. A pharmacologically acceptable acid addition salt of l-R-lower alkyl-3-amino-guanidine, in which R is N,N- alkylene-imino having from sin to eight chain carbon atoms, and in which the amino-guanidino group has the formula 4. A pharmacologically acceptable acid addition salt of a compound of the formula in which R is hydrogen, the letter n stands for one of the whole numbers 6, 7 and 8, and A is lower alkylene having from two to three carbon atoms and separating the amino-guanidino group from the N,N-alkylene-imino group by from two to three carbon atoms.

5. A compound of the formula in which R is methyl, the letter n stands for one of the whole numbers 6, 7 and 8, and A is lower alkylene having from two to three carbon atoms and separating the aminoguanidino group from the N,N-alkylene-imino group by from two two three carbon atoms.

6. A pharmacologically acceptable acid addition salt of a compound of the formula NH (clam) N-A-NH-O in which R is methyl, the letter 11 stands for one of the whole numbers 6, 7 and 8, and A is lower alkylene having from two to three carbon atoms and separating the amino-guanidino group from the N,N,-alkylene-imino group by from two to three carbon atoms.

7. A compound of the formula:

in which R is hydrogen, the letter 12 stands for one of the whole numbers 6, 7 and 8, and A is lower alkylene having from two to three carbon atoms and separating the amino-guanidino group from the N,N-alkylene-imino group by from two to three carbon atoms.

8. 3 amino 1 [2 (N,N heptamethylene-imino)- ethyl1-guanidine.

9. 3 amino 1 [2 (N,N-heptamethylene-imino)- ethylJ-guanidine hydriodide.

10. A member selected from the group consisting of compound having one of the formulae:

in which R is a member selected from the group consisting of hydrogen and methyl, the letter :1 stands for one of the whole numbers 6, 7 and 8, and A is lower alkylene having from two to three carbon atoms and separating the nitro-guanidine and nitroso-guanidine groups from the N,N-alkylene-imino group by from two to three carbon atoms, and acid addition salts thereof.

11. 1 [2 (N,N heptamethylene 3 imino) ethyl] -3- nitro-guanidine. 7

No references cited.

IRVING MARCUS, Primary Examiner. WALTER A. MODANCE, Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A 1-R-LOWER ALKYL-3-AMINO-GUANIDINE, IN WHICH R IS N,NALKYLENE-IMINO, IN WHICH ALKYLENE HAS FROM FOUR TO TEN CHAIN CARBON ATOMS, AND THE AMINO-GUANIDINO GROUP HAS THE FORMULA
 10. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUND HAVING ONE OF THE FORMULAE: 